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Etiology of inflammatory bowel disease: A unified hypothesis

Really good find Wildbill. So good it might complete the circle.
Here is another example for UC,same thing lowered bacteroides
http://www.ncbi.nlm.nih.gov/pubmed/21073731

You might want to look at this thread I have on oxygen in the colon how
it might relate to this,and perhaps provide an answer. Seems like all this
ties together. Inflammation,generates more oxygen in the colon iNOS/possible excess nitrates in diet,obligate anaerobes/bacteriodes die, trpsin/protease is not deactivated,facultative anaerobes grow and invade,more inflammation,tissue destruction.
Or excess nitrate in diet,might start the whole mess off.
Old Mike
http://www.crohnsforum.com/showthread.php?p=694401#post694401

here is something on saccharin and gut bacteria
http://www.ncbi.nlm.nih.gov/pubmed/2420077
 
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Thanks wildbill_52280 and Old Mike for sharing the info and thoughts.

As stated in the paper I published several years ago (Qin X. With the great complexity unveiling, can we still decipher the interaction between gut flora and the host in inflammatory bowel disease to find out the mechanism and cause? How? Inflamm Bowel Dis. 2008 Nov; 14(11):1607-8), I felt it would be an extremely difficult task in attempting to find out the mechanism and cause of IBD by comparing the abundance of each of the dozens of thousands species of gut bacteria in patients versus controls, then analyzing the unique features that each bacterial species possesses and the specific profile of response by the host that each bacterial species elicits. In contrast, in my opinion, the overall effect of this dysbiosis, such as the increased activity of digestive proteases in the lower gut, would be more easily assessed and may also be in fact more directly related to the pathogenesis of the disease; and this detrimental effect of dysbiosis may be easily corrected by certain strains of bacteria such as Bacteroides mentioned in wildbill_52280’s post (#203) and discussed in my earlier post (#170).
 
Here is the problem,as far as a bacteroides as a probiotic.
Is FT the only solution,or can we somehow regrow our own.
http://www.drmyhill.co.uk/wiki/Prob...ose_following_antibiotics_and_gastroenteritis

somewhat better article
http://www.drpompa.com/Health-Tips/probiotics-digestive-problems-digestive-disease.html

in the past I used to eat some dirt but was afraid of getting some pathogen from say rabbit poo,but perhaps

if you dig down you might be ok. You don't actually have to swallow the dirt,just hold it in your mouth and swallow the saliva.



Another way is perhaps with fermented cabbage,but a slightly different take.

You would have to have a fermentation lock,like they use to make wine to exclude oxygen,then some type of straw arrangement that is also sealed,once you get lots of bacteria going,suck out all the juice.

I suspect you can only due this once,since air would have to be let in to get the juice out of the straw,unless of course you use nitrogen to pressurize the container while drinking.

Then again you might just be able to drink the juice real fast without exposing it to too much oxygen.



There has got to be a way around this,hopefully by reducing iNOS and ROS the obligate anaerobes will grow better.
 
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In fact, the capability of inactivating digestive proteases seems just belonged to some very special strains of bacteria. For instance, a study showed that trypsin can be inactivated by Bacteroides distasonis E9 but not Bacteroides distasonis D4 (Ramare F, et al. Inactivation of tryptic activity by a human-derived strain of Bacteroides distasonis in the large intestines of gnotobiotic rats and mice. Appl Environ Microbiol. 1996 Apr;62(4):1434-6). Thus, as for the effective inactivation of digestive proteases, it may probably be achieved by targeted delivery of just a small amount of the right bacteria.
 
Here is an older paper on mucus and protease in the colon,not sure
if it has been referenced yet. It is cached so it does not format quite right.
Old Mike
Link
 
Thanks Old Mike for sharing the paper. It clearly demonstrated a similar scenario regarding the synergistic effect of digestive proteases and bacterial glycosides on mucus degradation. But the unified hypothesis discussed here further proposed that the increased proteases activity might be the result of poor inactivation due to the reduction of gut bacteria by dietary chemicals like saccharin and sucralose along with the improved hygiene condition in modern society. Thus it provided a possible ultimate explanation for the mystery of IBD.

Here I would like to share some updates.

I noticed a long-standing Special Requests for Proposals at Broad Foundation asking grant applications to look into the “Differences in IBD incidence between developing and developed countries” (http://broadmedical.org/funding/overview.html). I recently submitted a Letter of Interest entitled “Some food additives as the possible main cause of differences in IBD incidence between developing and developed countries” as the first step of the application, but was soon rejected. This is the third time I tried applying some grant from Broad Foundation. The first one was in late 2001, shortly after I found that saccharin may be an important causative factor for IBD, and the second one was in 2008 after I published a series of paper with further evidence showing the possible link and mechanism. All of them were rejected.

I saw a recently published paper in the journal of Inflammatory Bowel Disease showing the climbing incidence of pediatric IBD in the United States from 1997 to 2009 (Debruyn JC, et al. Nationwide Temporal Trends in Incidence of Hospitalization and Surgical Intestinal Resection in Pediatric Inflammatory Bowel Diseases in the United States from 1997 to 2009. Inflamm Bowel Dis 2013 Oct;19(11):2423-32). As demonstrated in Figure 2 and Figure 3 of my paper, it showed leveling off or even decreases in IBD in the United States as well as many other developed countries during later 1970s and early 1980s. I collect a series of more evidences suggesting the new round of accelerated increase of IBD in the US started since around early 2000s. For instance, in the conclusion of the paper by Ingle SB et al, it stated that “Although incidence rates of Crohn's disease and ulcerative colitis had remained relatively stable in Olmsted County between 1970 and 2000, the incidence of both conditions appears to have increased somewhat over the past 5 years” (Ingle SB, et al. Increasing Incidence and Prevalence of Inflammatory Bowel Disease in Olmsted County, Minnesota, During 2001-2004. Gastroenterology 2007;132:A19-A20). The Figure below shows the result of another study by Sewell JL et al (Hospitalizations are increasing among minority patients with Crohn's disease and ulcerative colitis. Inflamm Bowel Dis 2010;16:204-7), we can see the jump of IBD in Asians in the United States at the beganing of this new Millenium, suggesing a sudden introduction of some risk agents in their life. I feel people should pay great attention to this kind of peculiar changes, as the ultimate cause may just hide behind them. I submitted a letter to the editor to raise the concern, but it was also rejected. Again, the remarkable increase of IBD in early 2000s in the US shortly after its approval of sucralose in 1998. No matter it would be sucralose or something else, we need doing something to find its cause. Unfortunately, it seems hardly any people really interested to put some efforts on this.
 

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Thank you Xiaofa: Interesting info. You might find this paper also very interesting.
I believe that this is the same basic mechanism for UC, but in UC perhaps many different
agents may accomplish the same end result.
Old Mike
link
 
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Thank you to the main contributors to this thread.
It is epic!

When I look at the map of the 'incidence of crohns' globally,



England and America are the higest incidence.
It makes sense that it would spread from England to Europe via migration.
What is interesting is Australia and South Africa - mostly English people left England and went to these countries.
Maybe it is the English genetic that left England and went to America that assisted in making crohn's rampant in America moreso than anywhere else.

My question is - what are they doing in England, America, South Africa, Australia and all of Europe that they are not doing in Russia, India, Japan, China?

It kind of rules out smoking - because the chinese, japanese, russians, indonesians all smoke like chimneys.

anti-biotics : everyone uses antibiotics these days...?

assuming you have the 'gene' - it must be something in the environment of these countries which is setting it off...and it is very hard to go past foods.

do the russians, africans, chinese, japanese, indonesians and asians drink cows milk? I have no idea

do the russians, africans, chinese, japanese, indonesians and asians eat white bread?

white rice?

they all drink coca cola - so we can probably rule out sugar!

there must be a common link....

it frustrates me that between all of us we cannot work it out.

The technology is incredible right here that we can all communicate...

I personally think that it is something to do with genetics, anti-biotics overuse and diet...


But god i wonder about this chart....the global incidence....all those south africans came from england.....all the australians came from england....all the americans....sorry, came from england.....it must have started in England....what did england pioneer in food consumption???
 
Thank you Xiaofa: Interesting info. You might find this paper also very interesting.
I believe that this is the same basic mechanism for UC, but in UC perhaps many different
agents may accomplish the same end result.
Old Mike
link
Thank you Old Mike for sharing the info. I found it very interesting.


But god i wonder about this chart....the global incidence....all those south africans came from england.....all the australians came from england....all the americans....sorry, came from england.....it must have started in England....what did england pioneer in food consumption???
Yes, it is a very good question as why countries like Australia and South Africa but not many countries in Europe shared a similar patter of IBD as England. In fact, I have started the paper discussed here with the section entitled “Large commercial marketing of saccharin in 1887 and the emerge of clustered cases of ulcerative colitis since 1888, started from the United Kingdom”, which is further extended with three sub-sections: 1) The discovery of saccharin in 1878 from coal tar and its large-scale production and marketing since 1887; 2) The favorite use of saccharin in United Kingdom since 1887 but dislike or ban of saccharin in Germany and most of the other Western countries in the early years; 3) Emergence of clustered cases of ulcerative colitis since 1888, started from United Kingdom. In my opinion, this phenomenon probably is not related to gene (people in UK would be just originated from Europe) or the general food staff like bread or meat, but rather the attitude to some food additives such as saccharin originated from the coal tar.
 
Xiaofa: As you can see from the Pollen paper now that you have read it,that
the mucus is first degraded by protease,then the pollen can penetrate the mucus barrier
once this happens the immune system is then activated.
Whether the weakened mucus barrier in the gut is due to active digestive protease,bacterial protease,food mucus breachers,chemicals or toxins, or all of the above.
The same basic mechanism is taking place in the nasal passages and the gut,
the mucus is somehow breached and the antigens pollen/bacteria can present themselves to the immune system.
What bothers me is that non allergic people also have their nasal mucus breached but their
immune response does not cause allergies.
Both myself and my son have no allergies,yet both have UC.
By brother and daughter have pollen allergies but do not have UC.
Such a puzzle.
Old Mike
 
Yes, it seems nothing is straightforward and absolute in the real world. I saw your posts in another thread regarding polyethylene glycol (PEG) as a mucus breacher in the diet. PEG can easily penetrate the mucus layer largely because it shares some similar chemo-physical properties as mucus. As such, PEG has been used in some studies as surrogates for mucus and it actually showed some protective effect on things such as the ethanol-mediated mucosal injury of the stomach, etc.

Here are some studies:

Gutiérrez-Cabano CA. Protection by intragastric polyethylene glycol 400 in rat stomach against ethanol damage involves alpha2-adrenoceptors. Dig Dis Sci. 2000 Jan;45(1):105-9.


Wu L,et al. High-molecular-weight polyethylene glycol prevents lethal sepsis due to intestinal Pseudomonas aeruginosa. Gastroenterology. 2004 Feb;126(2):488-98.
 
Xiaofa: Yes I have read those studies. They were used in bulk. I am worried about the following in food and applied to vegetables, polysorbate which is a
PEG ester of sorbitan,peg-12,peg-8,both in toothpaste,PEG itself applied to vegetables. Once the polysorbate is digested it should free the PEG from the sorbitan, if so then the PEG is free to coat food and other micro particles,which can then penetrate the mucus. If the polysorbate reaches the colon intact then it will act as an emulsifier.

At anyrate the problem with both forms of IBD seems to be mucus.
Around 1920 when the incidence started to increase,we had pollution,chlorination,saccharin,canning,refrigeration,pasteurization,lecithin in foods,some industrial chemicals,no antibiotics,no pesticides,few surfactants,also industrial baking of bread using a yeast method as opposed to fermentation,start of nitrogen fertilizer,margarine.

Then after the second world war, many more chemicals and food additives,
antibiotics,pesticides.
We also have quite an increase in IBD.
So now we have more triggers,and triggers that vary with time.
For instance the type of pollution we have today,is much different than 100
years ago,both in chemical composition,and size of the particulate.
For this post my definition of trigger is a chemical or process in the body,caused by something in the enviorment which enables bacteria to breach the mucus.
Old Mike
 
simply - there must be something that is common place in England, America, Europe, South Africa and Australia - that is NOT happeneing in Russia, China, Japan, Africa.

I wonder what it is?

the way food is manufactured?
early childhood vaccines?
a type of food we eat that they dont?
something in the water?

some clever monkey must be able to connect the dots and work it out!??????????????
 
xiaofa, what's your opinion of parasites?
Thank you alfabeta for the interest in my opinion on parasites. I think it would be no surprising that parasites in the gut may have some effect on the immune system, etc, of the intestine, thus the pathogenesis of IBD. Some studies suggest some beneficial effect by the worms treatment, while some patients experienced worsening of the symptoms. More studies and clinical trials would be needed for and will eventually provide more accurate and comprehensive evaluation. Even parasites indeed have some protective effect, the irregular changes of IBD even in the developed countries and also many other evidence of discrepancies would suggest IBD are unlikely just the result of the elimination of the parasites along with improved hygiene in modern society but rather increased exposure to some other risk factors in the environment. Clothes or sun lotion may have some protection for sunburn, but sunburn will not occur without the exposure to the sun. There are big differences in IBD among the different countries. The differences in the sanitary condition and parasite infection would be much small among the big cities all over the world. This is just my personal opinion.
 
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Just some updates. The paper that was rejected by the journal of Inflammatory Bowel Disease as I mentioned in my earlier post (#210) was readily accepted for publication by the Journal of Clinical Gastroenterology and now is available online (Qin X. When and How Was the New Round of Increase in Inflammatory Bowel Disease in the United States Started? J Clin Gastroenterol. 2013 Nov 13. [Epub ahead of print]). I strongly feel we should pay great attention to the peculiar epidemiological changes of IBD, as there may lie the most valuable information for the ultimate mystery of what caused IBD. Any theory and hypothesis would have to be rigorously checked against these evidences, both pros and cons, to make a comprehensive evaluation.

The previous post just discussed the hot topic regarding the parasites and IBD. I have not expected the result may come out so quickly. The negative result of Trichuris Suis Ova (TSO) (the whipworm parasite of pigs) clinical trial as discussed in this forum (see: Whip worm study and Worms Flop in Crohn's Disease) is not surprising to me. The fantasy has lasted for a decade and generated so much expectation. The lack of efficacy is disappointing but nevertheless it makes us a step forward toward the truth.
 
I met with my GI today, sayin that I will start FMT any day now, he still say that it´s too early and that there are no evidence blablabla.

So I told him, like I did before, that there ARE studies for FMT and crohns and that I would send him the links. Are they all in this thread?
 
Hey, Xiaofa.

Can you quickly look at this:

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0052132

I didn't know this, but Maltodextrin is used as a bulking agent for sucralose.

Splenda, the maker of sucralose produces tons of the stuff every year and holds the majority of the market in the West, they use maltodextrin to bulk it.

Would need to read the composition more, but you're getting in a lot of maltodextrin when you consume sucralose.

It ties sucralose together with invasive E Coli.

Here's my invasive E Coli thread btw:

http://www.crohnsforum.com/showthread.php?t=52198

Normal people sometimes harbour minute colonies of invasive E Coli too, but something pushes AIEC over the edge in people with crohn's disease, the exact amounts of AIEC in people with Crohn's disease is much higher.

Many normal people are already infected with AIEC but they don't have crohn's disease because for some reason AIEC does not colonise in those people, you need some kind of trigger...some thing that makes them grow....genetic predisposition and sucralose can do this...
 
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It has to be something, crohn's disease didn't just appear from thin air, every country that industrialises get crohn's disease.

I looked up sucralose, it's produced with maltodextrin to bulk it.

edit: I mean saccharin, I already knew it of sucralose
 
I.e modulen ibd...
It's really hard to know what EN actually has in it, I argued with Nutricia about this and said to them that their EN has maltodextrin in it, meant for IBD.

And they said that only some has it and their packets of 028 does not.

So I agreed at first, because those packets contain dried glucose syrup, but dried glucose syrup is not made through just one method, and the name dried glucose syrup has a lot of ambiguity to it, you can use maltodextrin to bulk almost any simple sugar apparently.
 
Also, regarding the reason they actually bulk with maltodextrin...is twofold as far as I understand:

1. Maltodextrin is cheap as hell, bulking anything with maltodextrin brings down the price

2. When you bulk with maltodextrin you can avoid regulations, since some countries don't see it as a normal simple sugar, and you can claim you have "0 calories" and lots of halftruths that allow you to sell your product under false pretences
 
Well when I had modulen ibd or fortisip for that matter it started to make me worse, so now I avoid it like the plague, it's weird though coz even some vitamin supplements have maltodextrin in them, I thought there were different types of maltodextrin though? And while we are on the subject of AIEC, can anti-map kill AIEC?
 
Splenda, the maker of sucralose that uses maltodextrin to make it, is from Johnson and Johnson, that also makes infliximab.

There has to be some irony in there.
 
The argument against anti-MAP use was the Australia trial.

(not borody, another group)

http://download.journals.elsevierhealth.com/pdfs/journals/0016-5085/PIIS0016508507008013.pdf

Anyway, this was the biggest trial that refuted anti-MAP therapy, not enough in remission, no sustained remission, etc.

People have argued against that trial, that some capsules didn't open, that the trial did cause remission but the paper itself was overly negative (and they were kind of overly negative to be honest).

ANYWAY,

At the end of the study, they say this:

"Despite its broad-spectrum activity, the antimycobacterial antibiotic
regimen used in the Australian study is not particularly effective against Gram-negative bacteria. New therapeutic trials should target members of the intestinal flora, such
as Bacteroides and adhesive Escherichia coli, which have now been associated with CD by different groups throughout the world."


And they are right, anti-MAP therapy, while somewhat effective against MAP, is not really effective against E-Coli.

It's not ineffective, but if you were targeting E Coli you would use a different cocktail.
 
Also, I have to add something to their "intestinal flora" in relationship to E Coli.

While AIEC is present in the intestine, it is present in the form of biofilms and it does not "stay in the lumen", it enters the gut wall, it can do this through the peyer's patches. AIEC is very much an intracellular pathogen, although I admit it is also present in the lumen.

That's the reason they have tried things like rifaximin, because rifaximin is effective against gram negative and has low bioavailability, it doesn't get absorbed through the gut wall really (well it does, but minute amounts).

Anyway, I can go on about this for a number of pages, but I don't want to spam this thread.
 
Hey, Xiaofa.

Can you quickly look at this:

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0052132

I didn't know this, but Maltodextrin is used as a bulking agent for sucralose.

Splenda, the maker of sucralose produces tons of the stuff every year and holds the majority of the market in the West, they use maltodextrin to bulk it.
Thanks kiny for referring me this article and interest in my opinion on Maltodextrin. I felt this is a pretty good study with quite a lot experiments and interesting results. However, as for the suggested causative role of maltodextrin added as food additives (such as those in splenda) in Crohn’s disease, I felt there is something we would have to consider.

As described in the referred paper, maltodextrin is just the enzymatic and chemical degradation product of corn, potato or rice starch (http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052132). As starch constitutes 92% of cornflour, 85.8% white rice, and 66.8% wheat flour (http://www.kickas.org/ubbthreads/ubbthreads.php?ubb=showflat&Number=143543), people with these grains as the main food for energy source would probably generate much more maltodextrin-like molecules during digestion before the final breaking down of these starches to glucose. Although maltodextrin constituents the bulk of splenda, it would be still tiny compared with those generated from the rice or bread that people have used far before the emergence of IBD in last century and also consumed now in many developing countries where IBD is low. According to Wikipedia (http://en.wikipedia.org/wiki/Maltodextrin), “Maltodextrin is easily digestible, being absorbed as rapidly as glucose”. If this statement is correct, we may wonder how much of the small amounts of maltodextrin taking as additives may really reach the lower intestine, especially multiple recent studies have revealed that damage limited to the colon (Crohn’s colitis) has become the main form of Crohn’s disease.

Above is just my personal thought. I would like to hear how you think on this.
 
Ty, hm I don't know how similar maltodextrin broken down from a complex starch bond in the intestine would be compared to what splenda puts in their sucralose.

So why I'm interested is this study here that said:

http://www.ncbi.nlm.nih.gov/pubmed/11052483

"The number of patients with Crohn's disease has increased remarkably. The prevalence and the annual incidence of patients with Crohn's disease in Japan were estimated to be approximately 2.9 and 0.6 per 10(5) population in 1986, respectively, and 13.5 and 1.2 per 10(5) population in 1998."

And I also know that rates of MAP are much lower in Japan and actually went down, because unlike in the West, if a cow gets MAP in Japan, the farmer gets a reward for telling the government, basically they get the value of their cow back as if it was healthy. Compared to Europe and the US, the amount of MAP in cows in minuscule in Japan. But somehow the rates of crohn's disease went up dramatically.


There is another theory and it showed that an emulsifier called polysorbate 80 allows AIEC to translocate accross M-cells. M-cells are the caps on the peyer's patches in the small intestine that "sip" antigen content, usually bacteria, they're basically "mini lymph nodes" in the intestine.

http://gut.bmj.com/content/59/10/1331.full

There is another study about this, would have to find it again.

Crohn's disease is now most common (and afaik, has always been) around the teenage years, peyer's patches are most active around the teenage years, it is a very logic explanation why crohn's disease would be in the ileum (only place where peyer's patches really are), and why it would manifest itself around the teenage years.

Anyway, I really find it strange what happened in Japan over such a short period, because they have low MAP, their way of life didn't change really, only what they eat has changed dramatically, there are fast food joints everywhere in Japan now, I remember that 20 years ago, there were almost none in those same areas, oh well.
 
MAP is also found in ground beef, in the usa ground meat is usually made from culled cows,at least the bulk kind.
Anyway Japan imports a lot of meat for hamburger from Australia and
New Zealand, could this be the reason crohns increased while domestic
herds in Japan had low MAP.
MAP was a new disease first found in cows 1895,timelines with IBD fit well.
Being exposed to just the antigen or DNA may be enough to cause a problem,may
not even need to harbor live MAP,once antibodies are present.

Old Mike

LINK
 
Thanks kiny and Old Mike for sharing the thoughts and info. The increase in the incidence of Crohn’s disease in Japan from 0.6/100,000 in 1986 to 1.2 /100,000 in 1998 is still not that dramatic. Here is a Figure showing the number of IBD patients seen in a Saudi clinic during 1993 to 2009 in a study by Al-Mofarreh MA and Al-Mofleh IA published this year (Emerging inflammatory bowel disease in Saudi outpatients: a report of 693 cases. Saudi J Gastroenterol. 2013 Jan-Feb;19(1):16-22). We can see there was 0 or only 1 patient of Crohn's disease during 1993 to 2000; the number increased to 3 or 4 cases during 2001 to 2003, then jumped to 174 cases in 2009. Again this increase occurred shortly after the approval of sucralose in Saudi Arabia around 2000. Thus at least sucralose can be listed as a suspect. People would definitely need to put some effort to find out the cause behind this increase, no matter it turns out to be sucralose, emulsifier, MAP, or something else.
 
Crohn's disease is now most common (and afaik, has always been) around the teenage years, peyer's patches are most active around the teenage years, it is a very logic explanation why crohn's disease would be in the ileum (only place where peyer's patches really are), and why it would manifest itself around the teenage years.
Some studies demonstrated that damage limited to the colon (colonic Crohn’s disease) increased over time and has become the main form of Crohn’s disease. For instance, in Stockholm County, Sweden colonic CD increased from 15% during 1959-1964 to 32% during 1980-1989, and further to 52% during 1990-2001, while the ileocaecal CD decreased from 58% during 1959-1964 to 41% during 1980-1989, and to 28% during 1990-2001 (see: http://www.ncbi.nlm.nih.gov/pubmed/9391246/ and http://www.ncbi.nlm.nih.gov/pubmed/16440421). This is one reason I suggest ulcerative colitis and Crohn’s disease are likely just two symptoms of the same morbidity rather than two different disease as stated in my paper discussed here (here is the link). What are your explanations for the damage in the colon and increase in colonic CD over time?

MAP is also found in ground beef, in the usa ground meat is usually made from culled cows,at least the bulk kind.
Anyway Japan imports a lot of meat for hamburger from Australia and
New Zealand, could this be the reason crohns increased while domestic
herds in Japan had low MAP.
MAP was a new disease first found in cows 1895,timelines with IBD fit well.
As discussed in the previous post, there is a remarkable increase in Crohn’s disease in Saudi since early 2000s, while the change for ulcerative colitis is much less, suggesting the increase in CD is unlikely just due to raised awareness to IBD in the society or increased referral to that clinic. Is there any evidence that there is dramatically increased consumption of MAP contaminated meat or milk in Saudi? As discussed some early post, IBD is pretty high in Sweden, but MAP infection is very low in the herds. Is there any evidence suggesting Sweden imported and consumed large amounts of meat or milk from countries with heavy MAP infection? Just curious.

Being exposed to just the antigen or DNA may be enough to cause a problem,may not even need to harbor live MAP,once antibodies are present.
As for Johne’s disease in the herds or TB in human, the damage of the tissue seems indeed closely related to the amounts of bacteria existing. In the case of TB, antigen in the BCG vaccine would have helped generation of the protective immune response, and the antibody formed seems also beneficial rather than harmful to the body (See: Armando Acosta, et al. The Role of Antibodies in the Defense Against Tuberculosis). To my knowledge, nucleic acid (DNA and RNA) has been sold by some company as “superfood” with rejuvenative powers (here is an example). I knew this claim has been challenged by some scientists. On the other hand, is there any evidence that DNA can cause a problem to the body?
 
Xiaofa,here is a quick look at some of the questions you brought up on
beef imports and also MAP antigen,seems that timelines are suggestive.
Saudi beef imports chart,big increase since about 2000.
Old Mike

http://www.indexmundi.com/agriculture/?country=sa&commodity=beef-and-veal-meat&graph=imports

Australian beef is imported
http://halalfocus.net/saudi-arabia-at-saudi-food-importers-seek-brazilian-beef/

much from the EU prior to 2002 BSE scare now also a brazil BSE scare

http://www.fas.usda.gov/info/countrypages/sabfsit.pdf

Saudi milk imports increase dramatic around 2002.
https://knoema.com/atlas/Saudi-Arabia/topics/Food-Security/Food-Imports/Milk---Excluding-Butter

Sweden imports triple since 2000 beef from Ireland
http://www.bordbia.ie/industryservi...efimportscontinuestogrow.aspx?year=2012&wk=29

MAP antigen
http://www.ncbi.nlm.nih.gov/pubmed/23519342

http://www.crohns.org/articles/1999_08_115-9_cm.htm

CWD forms of MAP
http://www.paratuberculosis.info/images/stories/pdfs/14
 
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Just a little something I overheard today, when taking my kid to the pre-school to play with other kids. There was this chinese guy talking to a woman and he said something like "I know of this chinese family that moved from China to here (Sweden) and the children developed allergies. Then the oldest boy went to China for vacation to visit his grandparents and all the allergies went away. Then when he came back to Sweden the allergies re-apeared. So the whole family moved back to China.

Isn´t this a perfect example on how the microbiota works. I wonder what this boy was exposed to here in Sweden? I know that Swedes and Finnish people are the biggest milkconsumers in the world. Funny...that Sweden have the highest exalerating crohns incidents in the world!!! MAP? Did the boy retrieve the missing group of bacteria when he went back to China? And how fast did this shift occur.

Very interesting nevertheless.

Have a great weekend.
 
My gut is telling me that there is certainly something in the food that causes this piece of shit disease. Milkproducts or beef (McDonalds etc.)
 
The current theory which allows us to treat IBD with some decent success has been to suppress inflammation, and it has worked to reduce symptoms and cause remission in most patients. we must acknowledge that this theory is somewhat successful, but we don't yet know all the underlying mechanisms as to why. Further studies will likely reveal more information that will allow us to create better theories and models.

Here are two recent observations that may help explain why suppressing inflammation can decrease symptoms in IBD. in a nutshell, the chronic state of inflammation may exist as a first event in IBD, then slowly, a byproduct of inflammation called nitrate and nitrite now can feed pathogens and allows us to accumulate bacteria that may be harmful either from our environment, or feed pathogens that naturally exists in low levels in the gut , but are now much higher then they used to be.


Host-derived nitrate boosts growth of E. coli in the inflamed gut. 2013
http://www.ncbi.nlm.nih.gov/pubmed/23393266
Streptomycin-Induced Inflammation Enhances Escherichia coli Gut Colonization Through Nitrate Respiration
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705454/


So by inhibiting inflammation, nitrate and nitrate production is reduced, pathogens then reduce that cause diarhea and damage, and our symptoms reduce. This is still not a complete model or explanation as to how the disease works, but is more complete then before i believe. and that's why we still have issues controlling this disease as our knowledge is incomplete. but it is the inflammation that may precede alot of these events, so to explain that, i believe damage to the microbiome is a very good explanation as now we have information that suggests these bacteria turn inflammation off.


Commensal Clostridia: leading players in the maintenance of gut homeostasis
http://www.gutpathogens.com/content/5/1/23


Clostridium spp. belonging to clusters XIV and IV have also been reported to be strong inducers of colonic T regulatory cell (Treg) accumulation [89]. CD4+Foxp3+ Tregs are the most prominent regulatory cells in the body and are most abundant in the colonic lamina propria [90,91]. Here, their frequency among CD4+ T cells is notably higher than in other organs [89], suggesting that the intestinal microbiota may be involved in the accumulation of colonic Tregs. Several reports have determined that intestinal Foxp3+ Tregs are markedly affected by the intestinal microbiota [92]. A fraction of intestinal Tregs express T cell receptors that recognize antigens derived from the gut microbiota [93]. It has been established that these colonic Tregs play critical roles in intestinal immune homeostasis, suppressing systemic and mucosal immune activation to control intestinal inflammation, and contributing to maintaining tolerance towards gut microbiota [94,95]. Atarashi et al. showed that colonization of germ free mice with a defined mixture of 46 Clostridium strains belonging to clusters XIVa and IV induced the accumulation and differentiation of colonic Tregs [89]. Clostridium spp. were also able to promote increased expression of IL-10 in Treg [89], expression of matrix metalloproteinases (MMPs), as well as activation of TGF-β [96] and indoleamine 2,3-dioxygenase (IDO) in colonic epithelial cells [89]. Intestinal epithelial cells are crucial for the maintenance of innate and adaptive immune homeostasis in the gut. Moreover, even the colonization with altered Schaedler flora (ASF), which includes Clostridium clostridioforme, leads to the accumulation of Tregs within the colon [97]. Consistent with these findings, F. prausnitzii, which belongs to Clostridium cluster IV, increases IL-10 production from peripheral blood mononuclear cells in vitro[98]. How Tregs induced by commensal Clostridia can contribute to immune homeostasis in the intestine is an important question to address. Foxp3+ cells with TCRs specific for CBir1, a flagellin related to those of Clostridium cluster XIVa, induce IgA+ B cells in the intestine in order to reduce the mucosal uptake of microbiota-derived antigens and prevent systemic T cell activation [99]. Therefore, Clostridium spp. can affect the number and function of colonic Tregs, inducing naive CD4+ T cells to differentiate into antigen-specific colonic Tregs that are able to enforce immune tolerance towards commensal bacteria. It is interesting to note that even conventional T cells express TCRs specific for commensal antigens, and are potentially colitogenic if not completely suppressed by intestinal Tregs [100]. Notably, elevated levels of Clostridium clusters XIVa and IV in mice leads to resistance to allergy and intestinal inflammation in experimental models [89]. Conversely, the microbiota of individuals with chronic inflammation show lower bacterial diversity and it has been determined that Clostridium clusters IV, particularly F. prausnitzii, and XIVa are significantly less abundant in IBD patients compared to healthy subjects [14,98,101]. It is still unknown whether the decrease in Clostridia is a cause or a consequence of chronic inflammation in IBD patients and in autoimmunity, but we can speculate that they are necessary for immune homeostasis, contributing to the suppression of autoimmunity and deleterious inflammation in humans.
these are only some of the reasons which support the use a fecal transplant to restore the missing bacteria in IBD to treat or possibly cure IBD. here is more info on fecal transplants- http://www.crohnsforum.com/showthread.php?t=52400
 
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Xiaofa,here is a quick look at some of the questions you brought up on
beef imports and also MAP antigen,seems that timelines are suggestive.
Saudi beef imports chart,big increase since about 2000.
Old Mike

http://www.indexmundi.com/agriculture/?country=sa&commodity=beef-and-veal-meat&graph=imports

Australian beef is imported
http://halalfocus.net/saudi-arabia-at-saudi-food-importers-seek-brazilian-beef/

much from the EU prior to 2002 BSE scare now also a brazil BSE scare

http://www.fas.usda.gov/info/countrypages/sabfsit.pdf

Saudi milk imports increase dramatic around 2002.
https://knoema.com/atlas/Saudi-Arabia/topics/Food-Security/Food-Imports/Milk---Excluding-Butter
Thanks Old Mike for quickly finding out the information. Indeed, both Crohn’s disease (CD) and the import of beef and milk in Saudi increased during 2000s. However, there seems still some discrepancy between them: beef and veal meat imports increased from 68,000 in 2000 to 119,000 MT CWE (1.75 fold), milk import increased from around 52 during 1997 – 2002 to 73 kg/person/year in 2007 (1.4 fold), while Crohn’s disease increased from 0 – 1 before 2000 to 174 in 2009. Especially, the increased import of beef was largely from Brazil where CD is still relatively low. How to explain the extremely low CD before 2000 when the bulk of beef and meat imports being from Europe where the incidence of CD was pretty high?


According to the article, beef imports in Sweden tripled over 2000 to 2011. Then we may expect a successive increase of CD over this period. Interestingly, a recent study on paediatric IBD in Northern Stockholm County revealed that ulcerative colitis increased from about 1/100000 during 2002-2004 to 4 during 2005-2007, while CD decreased from about 10/100000 during 2002-2004 to 7 during 2005-2007 (Malmborg P, et al. Increasing incidence of paediatric inflammatory bowel disease in northern Stockholm County, 2002-2007. J Pediatr Gastroenterol Nutr. 2013 Jul;57(1):29-34). I suspected that this may be caused by a change of regulation by European Union in 2004 that reduced the maximum permitted level for cyclamate in soft drinks from 400 to 250 mg/L(Qin X. How to explain the discordant change of ulcerative colitis and crohn disease in adjacent or even the same regions and time periods. J Pediatr Gastroenterol Nutr. 2013 Nov;57(5):e30. You can find the story as how I got to this at my early post #182). I would like to learn if there is any other explanation.


I felt the damage of gut described in the first link above is more like the local inflammatory reaction of the skin in a positive TB test. It may need the presence of large amounts of highly concentrated antigens to induce a reaction like this. We may wonder if the small amount of MAP components in the beef or milk may cause such damage as CD.
 
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The current theory which allows us to treat IBD with some decent success has been to suppress inflammation, and it has worked to reduce symptoms and cause remission in most patients. we must acknowledge that this theory is somewhat successful, but we don't yet know all the underlying mechanisms as to why. Further studies will likely reveal more information that will allow us to create better theories and models.

Here are two recent observations that may help explain why suppressing inflammation can decrease symptoms in IBD. in a nutshell, the chronic state of inflammation may exist as a first event in IBD, then slowly, a byproduct of inflammation called nitrate and nitrite now can feed pathogens and allows us to accumulate bacteria that may be harmful either from our environment, or feed pathogens that naturally exists in low levels in the gut , but are now much higher then they used to be.


Host-derived nitrate boosts growth of E. coli in the inflamed gut. 2013
http://www.ncbi.nlm.nih.gov/pubmed/23393266
Streptomycin-Induced Inflammation Enhances Escherichia coli Gut Colonization Through Nitrate Respiration
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705454/


So by inhibiting inflammation, nitrate and nitrate production is reduced, pathogens then reduce that cause diarhea and damage, and our symptoms reduce. This is still not a complete model or explanation as to how the disease works, but is more complete then before i believe. and that's why we still have issues controlling this disease as our knowledge is incomplete. but it is the inflammation that may precede alot of these events, so to explain that, i believe damage to the microbiome is a very good explanation as now we have information that suggests these bacteria turn inflammation off.
Interesting explanation derived from fascinating theory published in prestigious journals. However, there would be still some questions that need to be answered:

1) At present, one of the most effective treatments for Crohn’s disease would be the anti-TNF therapy, which has also been very effective for the treatment of arthritis and psoriasis through a likely mechanism of direct inhibition on inflammation rather than growth of bacteria.

2) We know anti-TNF treatment increased the susceptibility of the infections by bacteria, fungus, virus, or parasites (here is a list). Can it really reduce the infection in the gut tissue where there are always large amounts of so many kinds of microbes in the lumen?

3) Some antibiotics would be able to exert more potent inhibition on bacteria like E. coli than just a reduced generation of nitrate/nitrite by the host. Why antibiotics are not so effective as anti-TNF therapy?
 
Some anti-biotics are indeed effective until the bacteria or pathogen builds resistance. Xia, have you heard of the SSI vaccine by qu biologics? I think their hypothesis/model is very promising. They use deactivated bacteria to stimulate new macrophage production, as they believe that persons with crohns are malfunctioning at this step and as a result not clearing the bacteria/pathogen
 
The mouse model that looks most like crohn's disease is currently this one from this study in Nature. I asked the researchers about this, and I don't believe any mouse models is closer to crohn's disease than this one. It has the transmural inflammation, it has a similar immune response, it has fibrosis. It's a mouse model with AIEC (E Coli) infection:

http://www.nature.com/ncomms/2013/130610/ncomms2957/full/ncomms2957.html

What doesn't really look like crohn's disease is the previous mouse model, which is still used for most tests, and that's the dextran sodium sulfate model.
 
What's interesting about E Coli I feel when people talk about it, is that you don't really need the "infection" part to make the model work with AIEC. You can carry AIEC in your intestine just like you can carry H Pylori, in very low numbers it doesn't affect you.

There was a dutch study that could predict crohn's disease in family members by checking anti-OmpC, in English that means antibodies against the outer membrane protein of E Coli bacteria.

 
Do you think colonic cd could still be due to AEIC?
Kind of, since it's often close to the ileocecal valve. I don't know really, they have found the bacteria in the colon too, it's just more rare, but it's not impossible.

AIEC is a pretty mobile bacteria too, it has no issue moving around in tissue like commensals have, a commensal stays deep within the lumen, the mucosa constantly moves around, it "glides around" so the bacteria can't adhere to it, it's not a static layer like most people think. AIEC is special in that it is excellent in adhering and penetrating the mucosa, most bacteria are incapable of doing that.
 
Thanks Joshuaaa and kiny for sharing the thoughts and info. Yes, antibiotic indeed worked at some situations, but seems just not as effective as anti-TNF. As discussed in my early post (see #74), I have actually expected that antibiotics should be more effective than they currently appeared to be, and factors like the impaired inactivation of digestive proteases may have confounded its real efficacy (Qin X. Impaired inactivation of digestive proteases: a factor that may have confounded the efficacy of antibiotics aimed at reducing the exposure to luminal bacteria and their components. Am J Gastroenterol. 2008 Nov;103(11):2955-6). As discussed in my earlier posts (see: post #157 and post #74) as well as in my paper published recently (Qin X. Does the association with NOD2, autophagy and some pathogens really mean Crohn's disease is caused by uncontrolled infection? J Crohns Colitis. 2013 Aug 13 [Epub ahead of print]) I personally felt Crohn’s disease is more likely accompanied by excessive rather than deficient immune response, which nevertheless is still elicited to the increased infiltration of gut bacteria or their debris, E. coli or other bacteria, along with compromised gut barrier function. As for a new drug, its efficacy would be ultimately determined by the clinical trials. Hope the trial on SSI may come out with good results.
 
Here is a new comprehensive review on protease and IBD.
Seemed slow to load.
Old Mike
http://www.wjgnet.com/1007-9327/pdf/v19/i43/7531.pdf
Thank you Old Mike for sharing the paper. It reads excellent, with more than 100 references from scientific journals. However, it omitted a discussion of a fundamental question: why antibiotics increased the risk of IBD, despite that it reduced gut bacteria and bacterial proteases as mentioned several times in the paper. This paper is of great interest to me, as I also suspected that proteases, not from the bacteria, but rather originated from the pancreas that failed to be inactivated in the lower gut due to a reduction in gut bacteria has played a critical role in the pathogenesis of IBD, which was first published more than a decade ago (Qin XF. Impaired inactivation of digestive proteases by deconjugated bilirubin: the possible mechanism for inflammatory bowel disease. Med Hypotheses. 2002 Aug;59(2):159-63) and discussed again in more detail in the paper discuss in this thread (Qin X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol. 2012 Apr 21;18(15):1708-22).

According to the paper cited by this review (Macfarlane et al. Contribution of the microflora to proteolysis in the human large intestine. J Appl Bacteriol. 1988 Jan;64(1):37-46), protease activities in human ileal effluent were approximately 20-fold greater than in normal faeces. Another cited paper (Gibson SA, et al. Significance of microflora in proteolysis in the colon. Appl Environ Microbiol. 1989 Mar;55(3):679-83) showed even big differences between the protease actitivy of the ileal effluent (would be mainly digestive proteases originated from the pancreas) versus feces (may be mainly from bacteria under conventional condition), being 1214 versus 20 when casein used as the substrate and 319 versus 11 when azocasine used as the substrate, respectively. Thus impaired inactivation of digestive proteases would be capable of causing a more detrimental impact on the lower gut. The dramatic increase of digestive protease activity in the lower intestine and increase risk of IBD with antibiotics and improved hygiene would be more supportive of the notion that impaired inactivation of the digestive proteases from the host seems likely played a more significant role in the development of IBD. This is my personal opinion and open for discussion.
 
Macfarlane also indicates that.
Comparative studies with faeces from a person who did not have a pancreas suggested that a substantial proportion of the proteolytic activity in normal faeces was of bacterial origin.

If we have dysbiotic bacteria which produce excess protease then perhaps
a problem.

It might also be possible that those with UC have a defect in host anti-protease
activity.

So perhaps there might be at least two other reasons that proteolytic activity
might be increased besides impaired inactivation of pancreatic protease.

I tend to believe there is a problem with excess protease the question is
what might be the real reason.


Old Mike
 
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Macfarlane also indicates that.
Comparative studies with faeces from a person who did not have a pancreas suggested that a substantial proportion of the proteolytic activity in normal faeces was of bacterial origin.
Yes, at normal condition almost all the proteases activity in the feces would be from bacteria, as the large amounts of digestive proteases secreted from the pancreas and reached the lower gut would be effectively inactivated. However, even all the fecal protease activity is from bacteria, according to the paper, it would still be just 20 casine units. However, a failure of inactivation of even a small fraction of the 1214 casine unit pancreatic proteases transited into the lower intestine could be much higher than 20.

If we have dysbiotic bacteria which produce excess protease then perhaps a problem.
I wonder is there any papers on this.

It might also be possible that those with UC have a defect in host anti-protease activity.
It is possible. Here is a study (Stone H, Pye A, Stockley RA. Disease associations in alpha-1-antitrypsin deficiency. Respir Med. 2013 Oct 14. pii: S0954-6111(13)00416-2). However, this would the problem originated from the host not gut bacteria.


I do not say bacterial proteases are completely innocent in IBD. However, the reduced gut bacteria and bacterial proteases but increased risk of IBD by antibiotics seems against a critical role of bacterial proteases in IBD. Is there any good explanation for this?
 
Thank you Xiaofa: The first paper I posted talks about increased bacterial
protease from dysbiotic bacteria even in the abstract.

http://www.wjgnet.com/1007-9327/pdf/v19/i43/7531.pdf

Xiaofa said:
"I do not say bacterial proteases are completely innocent in IBD. However, the reduced gut bacteria and bacterial proteases but increased risk of IBD by antibiotics seems against a critical role of bacterial proteases in IBD. Is there any good explanation for this"

I suggest that antibiotics also produce dysbiosis as a possible trigger for IBD.
But I also see your point.

Do you happen to know if when eating a low protein/no protein meal that the
pancreas outputs less protease. If so then one way to mitigate colitis might be to eat low protein, of course some are helped on a high meat paleo or SCD diet. Then also of course we can get diversion colitis,but that is perhaps not the same as UC.
Another theory is that our gut bacteria are actually being starved and becoming more virulent due to lack of proper food entering the colon, such as resistant starch.

Anyway there is no question that excess protease is a factor in UC.
I believe I have some papers posted in this thread on Camostat and BBI
protease inhibitors which showed good improvement in human UC small studies. So with something as simple as protease inhibitors we can see
improvement.
My personal trial with BBI constipated me for a week and a half, I became quite nervous so had to end it.
http://www.ncbi.nlm.nih.gov/pubmed/8358131
http://www.ncbi.nlm.nih.gov/pubmed/17551835

Mike
 
If you divert the fecal stream in people with crohn's disease who have surgery, they improve drastically, the same happens in people on TPN.

Stool consists of undigested macronutrients and lots of antigen in the form of bacteria. Stool by itself is very infectious. Either the intestine is reacting to the bacteria, or the stool friction causes loss of mucus membrane, which does happen, but since so many people have liquit stools when they're sick, I don't think that is what is going on. In fact I'm pretty sure I read somewhere that chronic diarrhea actually stimulates mucus production.

Also, stool is liquid when it's still in the ileum, it's only deeper in the colon that stool starts to lose it's liquid content.

Most intestinal infections can be seen in stool, even mycobacterial and intracellular infections, there is usually antigen within the stool.



.

If it was that simple that antibiotics cause crohn's disease through dysbiosis, the biggest abusers of antibiotics, China and Africa, would have the highest indices of crohn's diseasse. They have the lowest. Yes, China has crohn's disease cases, but compared to the West, they are still low, and China is a major abuser of antibiotics. China is probably the number one abuser of antibiotics.

The gut flora helps you protect from intestinal infections, and that would explain the correlation between crohn's disease and prior antibiotics use. But in Europe and the US, antibiotics use has gone down considerably, there are warning signs in every office in Europe that antibiotics should not be used for viral infections and should not be abused for microbial infections. And yet...crohn's disease keeps rising in the West.
 
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If you look at the recent genetic discoveries related to crohn's disease, every single one is related to handling of bacteria. Maybe instead of suggesting the issue is dysbiosis or lack of "good bacteria" and trying to treat people with probiotics, they should look at what happens when a crohn's disease patient gets an infection.

There is a good study from the 90s that showed that crohn's disease patients can not handle E Coli when it is infected in tiny slits in their forearm by causing small wounds (some type of sandpaper was used), they react very slow and bad to it because of macrophage deficiencies. This is their forearm, not their intestine. Controls had no issues clearing the E Coli, crohn's disese patients had lots of issue, macrophage deficiencies, decreased blood flow to the wound, cytokine deficiencies.

Maybe the question should be....can crohn's disease patients handle bacteria of any kind. pathogenic or not, can they even handle dead bacteria or would it be treated an as antigen.

.

Crohn's disease doesn't look like UC, at all, it actually looks like chronic granulomatous disease and intestinal TB.

Even mortality rates between these diseases show similarities, that latest study of increased mortality rates of crohn's disease patients versus UC, had to do with increased infections.

People and animals with immunodficiencies tend to be prone to intestinal infections, AIDS patients are not very prone to crohn's disease, interestingly, they tend to be protected from crohn's disease, it does happen, but rarely, but they are very susceptible to things like MAC infections.
 
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Thank you Xiaofa: The first paper I posted talks about increased bacterial protease from dysbiotic bacteria even in the abstract.

http://www.wjgnet.com/1007-9327/pdf/v19/i43/7531.pdf

Yes, it is stated in the abstract that “Reports of increased protease activity in stools from IBD patients support a possible mechanism for a dysbiotic enteric microbiota in IBD”. Indeed multiple studies showed increased protease activity and dysbiosis of the microbiota in IBD. However, I found most studies are related to the increased activity of digestive proteases like trypsin and chymotrypsin originated from the pancreas, a phenomenon that is also seen in people or animals treated with antibiotics or animals raised in germ-free condition, in which the amount of bacteria and bacterial proteases would be reduced or absent rather than increase. Despite that, it might be still possible that there exists some sort of dysbiosis in which the protease-producing bacteria become overgrowth amid a general reduction of gut bacteria. So I wonder if there was any study and paper having really demonstrated this.


Do you happen to know if when eating a low protein/no protein meal that the pancreas outputs less protease. If so then one way to mitigate colitis might be to eat low protein
Yes, here is a paper: HOWARD F, YUDKIN J. EFFECT OF DIETARY CHANGE UPON THE AMYLASE AND TRYPSIN ACTIVITIES OF THE RAT PANCREAS. Br J Nutr. 1963;17:281-94. It stated that “The control diet contained 47% starch, 18 % casein and 18 % fat. When the starch was increased to 67 % of the diet, there was a 40 % increase in the amylase activity of the pancreas and a 50 % fall in the trypsin activity. When the casein was increased to 67% of the diet, there was a 20% fall in amylase activity and a threefold increase in trypsin activity” and “The change in tryptic activity occurred in less Than 24 h”. Multiple studies also showed that meat and protein increased while vegetable and fruits decreased the risk of IBD. I have written some comments on this several years ago. Here is the paper: Qin X. Can meat and protein really increase, while vegetables and fruits decrease the risk of inflammatory bowel disease? How? J Crohns Colitis. 2009 Jun;3(2):136. I also suspected that some of the beneficial effect of enteral and parenteral nutrition may attributed to the reduced production of digestive proteases (Qin X. Reduced production of digestive proteases and the efficacy of enteral and parenteral nutrition on inflammatory bowel disease. Inflamm Bowel Dis. 2008 Jun;14(6):871), an area that awaits further study.
 
If you divert the fecal stream in people with crohn's disease who have surgery, they improve drastically, the same happens in people on TPN.
This prompt improvements seems against the notion that the damage of Crohn's disease is caused by the persistent uncontrolled infection of bacteria like MAP in the mucosa.

Stool consists of undigested macronutrients and lots of antigen in the form of bacteria. Stool by itself is very infectious. Either the intestine is reacting to the bacteria, or the stool friction causes loss of mucus membrane, which does happen, but since so many people have liquit stools when they're sick, I don't think that is what is going on. In fact I'm pretty sure I read somewhere that chronic diarrhea actually stimulates mucus production.
The continuous loss of mucus layer from gut surface is not only caused by the friction, but also some other factors like the reduced viscosity after more and more water coming in, the degradation by proteases and glycosides from the host and bacteria, etc.


If it was that simple that antibiotics cause crohn's disease through dysbiosis, the biggest abusers of antibiotics, China and Africa, would have the highest indices of crohn's diseasse. They have the lowest. Yes, China has crohn's disease cases, but compared to the West, they are still low, and China is a major abuser of antibiotics. China is probably the number one abuser of antibiotics.

The gut flora helps you protect from intestinal infections, and that would explain the correlation between crohn's disease and prior antibiotics use. But in Europe and the US, antibiotics use has gone down considerably, there are warning signs in every office in Europe that antibiotics should not be used for viral infections and should not be abused for microbial infections. And yet...crohn's disease keeps rising in the West.
As discussed early (see post # 66), the multiple large-scale epidemiological studies may suggest the positive link between antibiotics and IBD may probably be true. One alternative explanation for the low IBD in China and high in Western countries could be the exposure of some other factors in the west that make the effect of even such heavily used agents like antibiotics becomes trivial.
 
Crohn's disease doesn't look like UC, at all, it actually looks like chronic granulomatous disease and intestinal TB.
So, how you explain the close relationship between the epidemiological distribution of UC and CD in the world, and how you explain the increased risk of infection of TB, but improved healing of CD by anti-TNF-alpha and other immune suppression agents?

People and animals with immunodficiencies tend to be prone to intestinal infections, AIDS patients are not very prone to crohn's disease, interestingly, they tend to be protected from crohn's disease, it does happen, but rarely, but they are very susceptible to things like MAC infections.
This can be easily explained by the notion that CD is caused by an over-reaction rather than a deficiency of the immune system. What is your explanation for this?
 
So, how you explain the close relationship between the epidemiological distribution of UC and CD in the world, and how you explain the increased risk of infection of TB, but improved healing of CD by anti-TNF-alpha and other immune suppression agents?



This can be easily explained by the notion that CD is caused by an over-reaction rather than a deficiency of the immune system. What is your explanation for this?
That crohn's disease has macrophage and autophagy deficiencies is extremely well establised by hundreds of studies. I don't think that is something you can argue about.

The innate immune system is severely compromised in people with macrophage deficiencies.

Autophagy and the innate immune system were considered secondary to the adapative immune system in the past, most focus was on the adaptive response. Many recent studies have shown autophgay is directly involved in control of intracellular pathogens, and the innate immune is a lot more important than first assumed.

Immunosupressants used for crohn's disease, like imuran are actually used during certain infections to stop the destructive inflammation, in the inflammation affects organs and nerves, if you don't treat them with immunosupressants, they suffer from nerve damage or organ failure, regarless if you treat them with antibiotics or not. Some cases of TB are actually treated with immunosupressants.

If you treated some infections purely with antibiotics, you would cause nerve damage.

Why infliximab works, actually no one knows, all other anti-TNF alpha blockers like etanercept and the others that work for UC, don't work for CD.

.

Anyone who has looked at histology tissue, as I have from my own tissue, and compared it to tissue from UC, will tell you it looks nothing like UC. There are no granuloma in UC. Crohn's disease is transmural, it invovles things like fistula, granuloma, patchy inflammation.

It has didly squat to do with UC. The term "IBD" is really unfortunate.
 
over-reaction of the immune system
there is 0 evidence that crohn's disease is caused by an over-reaction of the immune system

people with crohn's disease are immunodeficient

I have crohn's disease and I actually have severe lymphopenia of CD4+, so do others with crohn's diseasse.

My crohn's disease is not "gone".

An overreactive immune system would be really nice for me, I have to use antibiotics for my lungs sometimes as a countermeasure so I don't get a lung infection.

The only world where crohn's disease is an overreactive immune system is fantasy world.

Crohn's disease: an immune deficiency state.
http://www.ncbi.nlm.nih.gov/pubmed/19437144

"A number of hypotheses have been proposed, most of which postulate a primary over-activation of the immune response, based on the pathological appearances of active Crohn's lesions. Interestingly, none of these theories have been mechanistically proven."

I have looked everywhere, not a single study has shown that crohn's disease or the patients have an overreactive immune system.

There is 0 evidence for that, nothing.

On the other hand, there are literally hundreds of studies that show macrophage, cytokine and autophagy deficiencies in crohn's disease. Immunodeficiencies. There is so much evidence for immunodeficiency in crohn's disease that you can't argue against it with a straight face.


Revisiting Crohn's disease as a primary immunodeficiency of macrophages
http://jem.rupress.org/content/206/9/1839.full

Mycobacteria in Crohn's disease: How innate immune deficiency may result in chronic inflammation
http://informahealthcare.com/doi/abs/10.1586/eci.10.29

Crohn抯 disease: Innate immunodeficiency
http://www.wjgnet.com/1007-9327/12/6751.asp[/URL

Vitamin D enhances macrophage function and improves killing of Crohn's associated E. coli
[URL="http://www.crohnsforum.com/showthread.php?t=47789"]http://www.crohnsforum.com/showthread.php?t=47789


Defective macrophage function in crohn's diseas
http://gut.bmj.com/content/60/Suppl_1/A143.2.abstract
 
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infliximab is actually deterimental to MAP survival btw

http://www.ncbi.nlm.nih.gov/pubmed/22398081

so is imuran and 6MP:

http://www.johnes.org/handouts/files/Shin_6MP.pdf

the world isn't as black and white as you think. immunosupressants are used extensively during infections, in fact the idea and basic need for immusupressants originated from infections, because the inflammation is in large part responsible for the tissue / organ and nerve damage in those people

the reason why some infections actually don't worsen on inflximab is because not every bacteria is the same, some cause very rapid cell division, others do not, some are intracellular, some are not, some can't handle an inflammatory environment, some exploit it

TB cause far more rapid cell divsion than something like MAP, which divides extremely slowly (that's why it takes months to culture it), even though they're both mycobacteria, they are very different bacteria, as a result, they also respond very differently to infliximab
 
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there is 0 evidence that crohn's disease is caused by an over-reaction of the immune system

people with crohn's disease are immunodeficient
Among the dozens of thousands of studies on Crohn’s disease, all effective treatments, from the different small molecules to biologics, are related to immune suppression, which would be a straight indication that CD is associated with an enhanced immune reaction.

infliximab is actually deterimental to MAP survival btw

http://www.ncbi.nlm.nih.gov/pubmed/22398081

so is imuran and 6MP:

http://www.johnes.org/handouts/files/Shin_6MP.pdf
We already have a detailed discussion on this early (see post #164). I would like to repost some of that post here.

"I also felt the notion that the high efficacy of the immune suppression agents like inflixmab and 6-MP is largely due to their bactericidal activity on MAP a fascinating idea, but I just wonder how this miracle occurred. A study (Greenstein RJ, et al. On the action of methotrexate and 6-mercaptopurine on M. avium subspecies paratuberculosis. PLoS One. 2007 Jan 24;2(1):e161) showed that although 6-MP have some inhibition on the growth of MAP, its activity is still much lower than some antibiotics like clarithromycin (4 ug/ml 6-MP versus 0.5 ug/ml clarithromycin to cause 80% growth inhibition of the bacteria). For the treatment of IBD, 6-MP is usually used in a dose below 100 mg/day and lasted for several weeks. However, in the study by Selby W, et al. (Antibiotics in Crohn's Disease Study Group. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology. 2007 Jun;132(7):2313-9), even clarithromycin used at 750 mg/day, along with 450 mg/day rifabutin and 50 mg/day clofazimine to treat the patients with Crohn’s disease for up to two years failed to show evidence of sustained benefit. I just cannot image how 6-MP, with much less bactericidal capability and used at a much lower dose and in such a short period can achieve the effective treatment for Crohn’s disease through the claimed killing of MAP".

It has didly squat to do with UC. The term "IBD" is really unfortunate.
Again, what is your explanation for the close relationship between the epidemiological distribution of UC and CD in the world?
 
Again, what is your explanation for the close relationship between the epidemiological distribution of UC and CD in the world?
It's not very close at all, crohn's disese and UC rates can differ greatly, double digit percentages, per country.

In some regions in canada diabetes rates are the same as crohn's disease rates.

Are we going to say diabetes is the same as crohn's disease...

that's not an argument, look at the clinical differences, UC and crohn's disease couldn't be farther apart

I remember we were talking about an article of V Kruiningen once, go ask him if crohn's disesase and UC are alike. He has shown multiple times through histology that they are completely different diseases.
 
I just cannot image how 6-MP, with much less bactericidal capability and used at a much lower dose and in such a short period can achieve the effective treatment for Crohn’s disease through the claimed killing of MAP".
Why either 6mp or infliximab works for crohn's disease is unknown at this point.

And no...it's not as simple as saying it lowers the immune response. Very strong TNF-alpha blockers like etanercept do nothing for crohn's disease.

My counterargument to you is that you are trying to prove that cohrn's disease can't be related to an infectious organism because you use immunosupressants.

As I have said before, immunosupression does not always worsen infections. In fact immunosupressants were made to treat infections.

Where do you think T cells in crohn's disease come from if it isn't from an APC. They don't magically appear from a diet or the gut flora. You need a pathogen.

You're jumping to conclusions and assumptions based on fact that aren't even true, just because you can't accept that crohn's disease, like almost any intestinal disorder involving inflammation, could be from pathogenic origin.
 
read this, tell me how you can interpret this as anything else than immunodeficiency

there is no question that this is immunodeficiency

I can show you hundreds of studies that show innate immunodeficiency in crohn's disease, but if you're not willing to accept it, I'm just wasting my time

the conclusion actually asks the same question you are asking......supressing the immune system when you are dealing with immunosupressed patients is probably not the best of ideas

and it probably isn't....but until there is better treatment, this is what patients have to use often....it stops the destructive inflammation and the ROS damage in the intestine

 
this is the evidence for AIEC:

http://www.crohnsforum.com/showthread.php?t=52198

You don't get to argue if it's there or not.......there are 60 something studies that show it's there........it's there...there's no argument

the argument that pathogens aren't causing inflammation in crohn's disease is over....the evidence is in, the only way to ignore the mountain of evidence is living on a secluded island in a bubble of denial

there's no argument anymore, you don't get to cherry pick articles
 
(Antibiotics in Crohn's Disease Study Group. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology. 2007
Not sure what you're trying to say here. That study recommended the use of antibiotics effective against gram- iin their conclusion nstead of broad spectrum against MAP because AIEC is more consistently found in crohn's diseasse patients.

AIEC is gram-
MAP is gram+

I never said MAP is a causative agent, I said that it is highly unlikely to me that a pathogen would not be involved. Granuloma, adaptive immune response, peyer's patches, NOD2, ATG16L1, skip lesions, onset fevers. All the telltale signs of an infectious agent.

It is also unlikely that an immunocompromised person would only be susceptible to a single "holy grail" bacteria, HIV patients are susceptible to a whole host of infections. Crohn's disease patients would be susceptible to intracellular bacteria that can exploit the macrophage deficiencies, macrophages that line the whole digestive tract coincidentally.

And the granuloma look like 2 drops of water like intestinal TB. Differentiating UC from crohn's disease is not hard, differentiating it from TB without staining biopsies and histology, is extremely hard.

Unlike something like UC, which again, is a very different disease.
 
Your thought process is sometimes nonsensical I feel. You can't just disprove a pathogen is involved by cherry picking a single study that used antibiotics. Go try that with people with resistant TB infections, go tell them they don't have TB just because your amoxicillin doesn't get rid of their TB. These arguments are beyond ridiculous and you're hurting people with crohn's disease by using them.

Mycobacteria and AIEC are extremely resistant type of bacteria, they create resistance in-vitro within hours.

The nature of crohn's disease, the constant relapses and inability to cure crohn's disease with over the counter braod spectrum, requires it to be resistant bacteria, otherwise a few weeks of flagyl would have us all cured.

Most people have moved on from the idea that there is one single holy grail bacteria causing crohn's disease, any immunodeficiency leaves you susceptible to multiple organisms.

Klebsiella and food borne bacteria like listeria and yersinia have also been associated with crohn's disease.
 
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It is a matter of sensitivity to any of the foods, additives, preservatives, sweeteners. I can't do any of them when I'm sick. When I get my immune system boosted, I can eat all of them and they don't bother me. So don't trust that what you ate yesterday is fine, it depends on how sick you are at the moment, and which direction it pushes you. If it is an irritant, it will get you the second, third, maybe fourth time. Also, look at what might be fed by these items, like candida. If you feed the bacteria what it wants to eat, it will thrive. Put back good bacteria as often as you can, in particular when you are doing antibiotics.
 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031217/

interesting article for you both to read, but to chime in, kiny is spot on, crohn's is definitely caused by an infection of some sort, all Koch's postulates have been fulfilled bar one which is unethically possible, whether it causes all cases - probably not, but like kiny said if you can't clear certain pathogens you're gonna end up with and inflammatory response. this being said out of the longest standing histological remissions that have been attained in CD they were achieved by either anti-map therapy and now most recently SSI vaccine - which left a patient in 100% histological - 4 years med free, the mechanism was to fix macrophage function so the innate immune system can do its job properly and clear out pathogenic bacteria. fecal transplant has also lead to sustained remissions, I don't know if it was restoring intestinal balance or through some sort of stimulation of peyers patches... there is soooo much still unknown, but just because immune suppressants work it doesn't mean its an auto immune disease, that shouldn't even be argued anymore its just creating false miss understanding, or making people bark up the wrong tree... absence of proof is not proof of absence
 
I think what it proves is rather simple, these cases are not all Crohn's, and many of the other cases are not diagnosed correctly. Mine is a good example. I have a pseudo-Crohn's because my immune system is trashed. Boosting it fixes my issues. How many people out there might be in the same situation? Too many if you ask me. The doctors were very quiick to just give me Crohn's medicines and suppress my already messed up immune system. Wrong thing to do, they almost killed me in the process. I had to be my own advocate and search for answers. I finally got to an immunologist and we figured it out before the doctors killed me with drugs I didn't need. Moral of the story is to be careful and not assume that doctors know everything or have it right. If you aren't reacting well to medications, and you get worse, make it a point to find out what it really is before you just accept that the doctors are always right. Look at the bug they finally found for stomach ulcers. I feel soon they will discover more of these bugs are causing issues for many of you. And some of you have genetic issues that make your digestive tract have problems, and some of you will find out you are just allergic to certain foods or medicines, and others will find that they have other issues. Just don't roll over and accept that the doctor is right unless the treatment is working.
 
Dur thanks so much for posting, my crohns has never been 100% crohns on histology, can you please tell me what your immunologist looked for? How are you now, symptom wise etc and colonoscopies findings recently? If you don't mind sharing
 
Frankly, I am quite surprised that there were people even denying the close relationship between Crohn’s disease and ulcerative colitis, with the fact that quite a portion of IBD patients cannot be classified as either CD or UC and misdiagnosed among these two frequently occurred. Not only they shared a certain pattern of epidemiological distributions, a recent so-called “to-date largest microarray gene expression study on IBD” demonstrated lack of major differences between Crohn's disease and ulcerative colitis by whole genome gene expression meta-analysis of inflammatory bowel disease colon mucosa. Here is the study:


PLoS One. 2013;8(2):e56818. doi: 10.1371/journal.pone.0056818. Epub 2013 Feb 13.

Whole genome gene expression meta-analysis of inflammatory bowel disease colon mucosa demonstrates lack of major differences between Crohn's disease and ulcerative colitis.

Granlund Av, Flatberg A, Østvik AE, Drozdov I, Gustafsson BI, Kidd M, Beisvag V, Torp SH, Waldum HL, Martinsen TC, Damås JK, Espevik T, Sandvik AK.

Author information

Abstract

BACKGROUND:

In inflammatory bowel disease (IBD), genetic susceptibility together with environmental factors disturbs gut homeostasis producing chronic inflammation. The two main IBD subtypes are Ulcerative colitis (UC) and Crohn's disease (CD). We present the to-date largest microarray gene expression study on IBD encompassing both inflamed and un-inflamed colonic tissue. A meta-analysis including all available, comparable data was used to explore important aspects of IBD inflammation, thereby validating consistent gene expression patterns.

METHODS:

Colon pinch biopsies from IBD patients were analysed using Illumina whole genome gene expression technology. Differential expression (DE) was identified using LIMMA linear model in the R statistical computing environment. Results were enriched for gene ontology (GO) categories. Sets of genes encoding antimicrobial proteins (AMP) and proteins involved in T helper (Th) cell differentiation were used in the interpretation of the results. All available data sets were analysed using the same methods, and results were compared on a global and focused level as t-scores.

RESULTS:

Gene expression in inflamed mucosa from UC and CD are remarkably similar. The meta-analysis confirmed this. The patterns of AMP and Th cell-related gene expression were also very similar, except for IL23A which was consistently higher expressed in UC than in CD. Un-inflamed tissue from patients demonstrated minimal differences from healthy controls.

CONCLUSIONS:

There is no difference in the Th subgroup involvement between UC and CD. Th1/Th17 related expression, with little Th2 differentiation, dominated both diseases. The different IL23A expression between UC and CD suggests an IBD subtype specific role. AMPs, previously little studied, are strongly overexpressed in IBD. The presented meta-analysis provides a sound background for further research on IBD pathobiology.
 
Very interesting, thanks for posting, did you happen to read the link I posted above? It is quite a long paper
Yes, I read this paper before. That paper (Pierce ES. Ulcerative colitis and Crohn's disease: is Mycobacterium avium subspecies paratuberculosis the common villain? Gut Pathog. 2010 Dec 17;2(1):21) proposed that not only Crohn's disease but also ulcerative colitis may be caused by MAP, a notion that further complicated the MAP controversy.

People have suspected that Crohn's disease may be caused by MAP largely because it shared some clinical and histological similarities with Johne's disease, such as the existence of inflammatory granulomas, a characteristic feature for CD. Compared to CD, similarities between UC and Johne's diseases are much less. Crypt abscesses, the characteristic changes in UC, are composed of large amounts of gut bacteria other than MAP and neutrophils, diminished a critical role of MAP in the inflammation of the tissue. The rate of MAP and its related parameters are also lower in UC. Even the discrepancies between CD and Johne's disease have caused so big controversy. The notion that UC may be also caused by MAP would be even more controversial.
 
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To my knowledge, the notion that Crohn’s disease may be caused by immune deficiency indeed draw quite attention years ago. People have even tried to develop the drug sargramostim, also known as granulocyte macrophage colony stimulating factor (GM-CSF) that stimulates stem cells to produce granulocytes and monocytes to boost the immune system. Unfortunately, the clinical trials failed to show much effect versus placebo.

Here is a paper on this:

Cochrane Database Syst Rev. 2011 Nov 9;(11):CD008538. doi: 10.1002/14651858.CD008538.pub2.

Sargramostim (GM-CSF) for induction of remission in Crohn's disease.

Roth L, Macdonald JK, McDonald JW, Chande N.
Author information
London Health Sciences Centre - Victoria Hospital, London, Canada.


Abstract

BACKGROUND:
Crohn's disease is an inflammatory condition of the gut, thought to involve an overactive immune response to gut flora. A novel theory postulates possible immunodeficiency as a cause, and aims to use sargramostim (granulocyte macrophage colony stimulating factor, GM-CSF) to boost the immune system in an effort to test this hypothesis.

OBJECTIVES:
The primary objectives were to determine the efficacy and safety of sargramostim for induction of remission in patients with clinically active Crohn's disease.

SEARCH METHODS:
A systematic search of MEDLINE, EMBASE, and CENTRAL was conducted from inception to April 2011. Reference lists of relevant review articles were also searched. Trial registries and abstract databases including Digestive Diseases Week (1980-2010) and United European Gastroenterology Week (2005-2009) were searched to identify studies published in abstract form.

SELECTION CRITERIA:
Randomized controlled trials of sargramostim for the treatment of patients with active Crohn's disease were considered for inclusion.

DATA COLLECTION AND ANALYSIS:
Data from selected articles were extracted and the Cochrane Risk of Bias tool applied independently by two authors. The primary outcome was induction of clinical remission as defined by a Crohn's Disease Activity Index (CDAI) of < 150 at the end of treatment. Secondary outcomes included clinical responses measures on the CDAI and safety outcomes. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes, in most cases using a random effects model due to high heterogeneity.

MAIN RESULTS:
Three studies were identified, 2 published as full papers and one in abstract form (537 patients). The risk of bias was low for the 3 included studies. There was no statistically significant difference in the proportion of patients (GM-CSF 25.3% versus placebo 17.5%) who achieved clinical remission (RR 1.67; 95% CI 0.80 to 3.50; P = 0.17; 3 studies; 537 patients). There was no statistically significant difference in the proportion of patients (GM-CSF 38.3% versus placebo 24.8%) who achieved a 100-point clinical response (RR 1.71 95% CI 0.98 to 2.97; P = 0.06; 3 studies; 537 patients). There was no statistically significant difference in the proportion of patients (GM-CSF 54.3% versus placebo 44.2%) who achieved a 70 point clinical response (RR 1.23; 95% CI 0.83 to 1.82; P = 0.30; 1 study; 124 patients). There was no statistically significant difference in the proportion of patients (GM-CSF 95.8% versus placebo 89.3%) who experienced at least one adverse event (RR 1.07; 95% CI 0.99 to 1.16; P = 0.08; 2 studies; 251 patients), or serious adverse events (GM-CSF 12.0% versus placebo 4.8%; RR 2.21; 95% CI 0.84 to 5.81; P = 0.11; 2 studies; 251 patients). The incidence of bone pain, musculoskeletal chest pain, and dyspnea were higher in patients treated with sargramostim compared to placebo. Other adverse events commonly associated with sargramostim such as pulmonary capillary leak syndrome, pulmonary edema, heart failure, fever, and neurotoxicity were not reported in these studies.

AUTHORS' CONCLUSIONS:
Sargramostim does not appear to be more effective than placebo for induction of clinical remission or clinical improvement in patients with active Crohn's disease. However, the GRADE analysis indicates that the overall quality of the evidence for the primary (clinical remission) and secondary outcomes (clinical response) was low indicating that further research is likely to have an impact on the effect estimates.
 
Dur thanks so much for posting, my crohns has never been 100% crohns on histology, can you please tell me what your immunologist looked for? How are you now, symptom wise etc and colonoscopies findings recently? If you don't mind sharing
My immunologist started me with tests for the immune system, out of the few they are aware of, they can't manipulate them all. Lucky me it was my iga system, treated by plasma infusion. My allergies also went from a positive reaction to no reaction after IgA treatment.
 
Dur thanks so much for posting, my crohns has never been 100% crohns on histology, can you please tell me what your immunologist looked for? How are you now, symptom wise etc and colonoscopies findings recently? If you don't mind sharing
The VA took my infusions away after reaching what they called a stable level. 2 years later I am back to suffering without it, and struggling with doctors to get treatment. It is very expensive. And now the fight to get treated has started again
 
close relationship between Crohn’s disease and ulcerative colitis
there is no close relationship, go look at histology pictures and show me the close relationship

you need to stop cherry picking articles also, there's also studies that pointed out the ridiculousness of grouping these 2 diseases together, one compared it to comparing bronchitis it TB lung infections...they're very very different disease

not sure why you are even writing papers if you think they are similar, go actually look at histology slides, put them side by side and tell me the diseases are the same, I have done so for my own biopsies, they look nothing like UC, the crypts and granuloma are nothing like UC, if you don't believe me that they are very different, go ask a histologist, they'll tell you and show you
 
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To my knowledge, the notion that Crohn’s disease may be caused by immune deficiency indeed draw quite attention years ago.
years ago?

I have no idea why you come to a crohn's disease forum if you live in a bubble of denial, you're not helping.

If you want to blame both UC and crohn's disease on some diet and ignore the massive amount of data about immunodeficiency related to crohn's disease and bacterial involvement, studies from nature, the lancet, BMJ, immunodeficienies related to autophgay, NOD2, ATG16L1, macrophage deficiency, VDR, interleukin 23, be my guest, don't expect most people to take you serious, you're quickly losing any respect I had for you. You cherry pick articles and you ignore massive data that shows genetic differences between UC and crohn', fistula, skip lesions, granuloma, transmural inflammation, pathological differences between the 2, treatment differences, antibiotics use for crohn's disease, and immunodeficiencies in crohn's disease. The studies you made consist of guesswork and controversial titles, often ignoring established data, just so your hypothesis makes sense. A lot of your studies say "in my opinion", you never sway from that opinion, you never take data that speaks against that "opinon" into account. They're not studies, they're opinon pieces.


2011
Defective innate immunity in inflammatory bowel disease
http://www.ncbi.nlm.nih.gov/pubmed/21483259


"Recent advances continue to highlight defects in innate immunity in Crohn's patients. Similar abnormalities may extend to other granulomatous disorders, but not diseases such as ulcerative colitis."


Believe it or not, UC does not look like crohn's disease. It can look a lot like chronic granulomatous disease and intestinal TB.



2013
Crohn's as an immune deficiency: from apparent paradox to evolving paradigm.
http://www.ncbi.nlm.nih.gov/pubmed/23256761


2013
Impaired autophagy leads to abnormal dendritic cell-epithelial cell interactions.

http://www.ncbi.nlm.nih.gov/pubmed/22981596

2012
Evidence from genetics for a role of autophagy and innate immunity in IBD pathogenesis.

http://www.ncbi.nlm.nih.gov/pubmed/22796792

2012
Defects in autophagy favour adherent-invasive Escherichia coli persistence within macrophages leading to increased pro-inflammatory response.
http://www.ncbi.nlm.nih.gov/pubmed/22309232

2010

NOD2 polymorphisms in clinical phenotypes of common variable immunodeficiency disorders.

http://www.ncbi.nlm.nih.gov/pubmed/20646002

2011
Defective macrophage function in crohn's disease: role of alternatively activated macrophages in inflammation
http://gut.bmj.com/content/60/Suppl_1/A143.2.abstract
 
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there is no close relationship, go look at histology pictures and show me the close relationship
Yes, the symptoms and histology of TB of the gut may quite similar as Crohn’s disease, but very different from TB in the lung, brain, kidney and bone. However, no matter in which organ, TB can be effective treated by anti-TB antibiotics, but anti-TNF alpha and other immune suppression agents effective for Crohn’s disease would execrated TB. Instead, CD and UC shared many similar treatments. SO CD and UC but not TB are more similar in nature.
 
Instead, CD and UC shared many similar treatments. SO CD and UC but not TB are more similar in nature.
Plenty of diseases are treated with TNF-alpha blockers, that does not in any share or form mean they are similar.

I've said a few posts back that your thought process is very hard to argue with because you base all your theories on nonsensical evidence.
 
great, you're choosing your words more carefully, "certain"..there is considerable differences between UC and crohn's disease rates in most countries
Do you know what the "certain pattern" here mean? It does not mean the difference of incidence between UC and CD, rather it means always UC starts to appears first followed by CD, but over time CD tends to catches up and even exceeds UC.
 
If you want to blame both UC and crohn's disease on some diet and ignore the massive amount of data about immunodeficiency related to crohn's disease and bacterial involvement, studies from nature, the lancet, BMJ, immunodeficienies related to autophgay, NOD2, ATG16L1, macrophage deficiency, VDR, interleukin 23, be my guest, don't expect most people to take you serious, you're quickly losing any respect I had for you.
Looking back human history, when had people respected new theory? Are these important?

A lot of your studies say "in my opinion", you never sway from that opinion, you never take data that speaks against that "opinon" into account. They're not studies, they're opinon pieces.
Yes, those are indeed just my opinions that I hope may bring people some new thinking. As I stated in my very early post, even Einstein made mistakes, and my opinion is always ready to adjust against new facts that emerge. On the other hand, the validity of my opinion and hypothesis would be also only determined by the facts that are accumulating.
 
I think what is way overdue, is breaking the broad approach to any of these diseases. I think we have similar symptoms and different causes, and the big mistake is clumping things together. My doctor was way too quick to base his findings on symptoms, not facts. The facts took 10 years to uncover because we trust that doctors are smart enough and concerned about our health. Generally they expect the medicines to work, if they do, great. If they don't more testing should be number one. Insist on it, the more data, the better it will get.
 
Plenty of diseases are treated with TNF-alpha blockers, that does not in any share or form mean they are similar.
In addition to IBD, TNF-alpha blockers like Infliximab are also used for the treatment of psoriasis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis. All these are regarded as autoimmune disease in nature.
 
In addition to IBD, TNF-alpha blockers like Infliximab are also used for the treatment of psoriasis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis. All these are regarded as autoimmune disease in nature.
That's right, many are, and to date, there is no real evidence crohn's disease is an autoimmune disease

An autoimmune disease requires a self-antigen.

Crohn's disease does not fulfill Witebsky's postulates.

In fact, just to point out once against how different UC and crohn's disease are, in UC there are self-antigen, colonic epithelial cells. In crohn's disease there are not, people who say there are tend to bend the definition of self-antigen quite a bit.

If the ileum epithelial cells or the gut flora was an antigen in crohn's disease, you would have inflammation everywhere, and you don't, there's skip lesions.........unlike....once again....UC.

UC has lumen inflammation, extremely specific to the colon, they have no fistula, no transmural inflammation, it does not discriminate, there are no skip lesions, the whole organ is inflamed. Crohn's disese is very different, you have granuloma, crypt look different, you have transmural inflammation, fistula. Different disease.

UC actually has hallmarks of an autoimmune disease, it non-discriminately affects the whole organ, unlike in crohn's disease.


There might be a cross reaction, E coli and Klebsiella could be causing cross reactions, but if it was directed at tissue, the whole ileum would be inflamed, and once again, if you look at crohn's disease pathology, they're skip lesions, doesn't look like an autoimmune response in any shape or form.


What’s in a name? The (mis)labelling of Crohn’s as an
autoimmune disease

http://211.144.68.84:9998/91keshi/Public/File/36/376-9736/pdf/1-s2.0-S0140673610602826-main.pdf
 
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If you believe all these diseases are "similar"...you're welcome to point out to us how etanercept that works for all these diseases does not work for crohn's disease.
 
Xiaofa: Thank you for the paper on trypsin output from the pancreas.
I may start to eat more starch and less meat.
Of course we have macrophage protease,and other proteases to worry about also.

Old Mike
 
Xiaofa: Thank you for the paper on trypsin output from the pancreas.
I may start to eat more starch and less meat.
Of course we have macrophage protease,and other proteases to worry about also.

Old Mike
I would like to thank you for sharing the thoughts and info.

Be careful that the protease theory remains a hypothesis to be tested.

Best wishes,

Xiaofa
 
That's right, many are, and to date, there is no real evidence crohn's disease is an autoimmune disease

An autoimmune disease requires a self-antigen.
The inflammation of the gut may be caused by uncontrolled proliferation of bacteria infiltrated into the mucosa. At such a situation, we should see quite a number of bacteria in the cells like macropahges in the mucosa and lymph nodes under microscope, not just detected by PCR after billions of times of amplification of the signal. The scarcity of bacteria and effective treatment by agents like anti-TNF seems more fit into the pattern of autoimmune disease. We should realize that not like the joint and some other organs deep inside the body, there are always large amounts of luminal contents that contain many kinds of harmful agents in the gut. Thus, it may even not need the existence of a self-antigen, as the increased infiltration of lipopolysaccharides (LPS, or endotoxin) and other bacterial products or antigens from the diet might be enough to provoke an enhanced immune reaction.

Again, this is just my personal opinion.
 
If you believe all these diseases are "similar"...you're welcome to point out to us how etanercept that works for all these diseases does not work for crohn's disease.
There are actually some difference between etanercept and anti-TNF α antibodies like infliximab: according the description, etanercept is a fusion protein produced by fusing the TNF receptor to the constant end of the IgG1 antibody, while infliximab is an antibody to TNF α. One explanation I think of regarding the difference of efficacy between these two would be that each infliximab molecule would be capable of binding and inactivated one TNF α, while the efficacy of etanercept to trap and inactivate TNF α would depand on the ratio of etanercept (the introduced exogenous TNF α receptors) to the amounts of endogenous TNF α receptor inside the body. If the exogenous and endogenous receptors are equal, only half of the administrated etanercept may bind a TNF α. If the endogenous receptors are 10 times in number of the injected etanercept, only about 1/10 of administrated etanercept may bind a TNF α. The gut has a large number of immune cells and the inflammation of gut may have caused a huge increase in endogenous TNF α receptor, thus a big variation and low efficacy of etanercept. This is just a speculation for a tentative explanation.
 
The inflammation of the gut may be caused by uncontrolled proliferation of bacteria infiltrated into the mucosa. At such a situation, we should see quite a number of bacteria in the cells like macropahges in the mucosa and lymph nodes under microscope, not just detected by PCR after billions of times of amplification of the signal.
You can't aways accurately detect leprosy, can't culture it really without a host. If people are helped through antibiotics, and they are, you linked a single study, cherry picked. There are plenty of studies that have shown the benefit of cipro-flagyl, not just for fistula, as treatment, cipro happens to be very effective against E Coli. What does it matter if you can't find a holy grail bacteria if antibiotics helps, the patients don't care. AIEC is there, why not treat it. There's a lot of things that are far more dangerous than treating ppl with antibiotics, regardless of resistance.

Avoiding to treat people because you can't find a holy grail bacteria would have killed thousands of lepers.

If there's a primary macrophagy deficiency and autophagy deficiencies, you would get disseminated bacteria, you'd end up with lots of antigen that is really hard to detect. You'd have non-stop APC signaling lymphocytes and never be able to fully clear the antigen causing all the inflammation.

Microparticles so common in the West would make it far worse. It would be really hard to find one single culprit after a while.

It's also a fallacy that you "need lots of bacteria"...you don't need much to get an inflammatory reaction going. Immune cells can replicate by the thousands per second. You don't need much to set off an adaptive immune response, the intestine is lined from top to bottom with macrophages, the small intestine is lined with peyer's patches. Look at what happens with other diseases of immunocompromised patients, a minor infection can quickly get out of control if they don't use preventive medication.
 
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You can't aways accurately detect leprosy, can't culture it really without a host.
Leprae is indeed difficult to culture. However, as I discussed with you about one year ago in a post in another thread, Gerhard Henrik Armauer Hansen in Norway had announced back in 1873 the discovery of Mycobacterium leprae in the tissues of all sufferers, with just a "new and better" microscope, without the special stains developed by Albert Neisser and others later. Here, I would like to repost that post here.

“Thanks kiny for sharing the thoughts. I admired the great efforts you and many other patients in this forum took, trying so hard to understand the disease. The body is very complex. Apparently, it is not easy to read through the many research papers with the many jargons.

Frankly, my intention is not to provoke sentimental arguments, although I have a lot of strong “scientific” evidences for both sides of the MAP controversy for an endless debate. Rather I think we should ponder thoroughly, deeply and carefully over the many conflicting “facts” to make a more accurate assessment and insightful judgments to figure out the likely true nature of the disease.

I do not think finding MAP in the blood is a trivial thing. The long lasting MAP controversy would actually largely attribute to the scarce of MAP found in the patients, which is in fact in great contrast with the situations in the Johne’s disease, M Leprae and H Pylori. Yes, we still failed to find out the right condition for culturing M Leprae in vitro. However, Gerhard Henrik Armauer Hansen in Norway had announced back in 1873 the discovery of Mycobacterium leprae in the tissues of all sufferers, with just a "new and better" microscope, even without the special stains developed by Albert Neisser and others later (http://en.wikipedia.org/wiki/Gerhard_Armauer_Hansen). This had been also before the discovery of Mycobacterium tuberculosis by Robert Koch in 1882 (http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis) and the discovery of Johne’s disease by Heinrich A. Johne in 1905 (http://en.wikipedia.org/wiki/Paratuberculosis). The existence of H. Pylori (the spiral-shaped bacteria) in the lining of the human stomach had been found by German scientists back to 1875, a century before Barry Marshall and Robin Warren approved they are the key causative factors for peptic ulcers in 1980s (http://en.wikipedia.org/wiki/Helicobacter_pylori) . As we know, large amounts of MAP can easily be found in the feces and tissues of Cattle with Johne’s disease and cultured with the standard methods established long time ago. It is the scarce of MAP in the feces and tissue of Crohn’s disease made the report of successful culture of higher rates of viable MAP in the blood of Crohn’s patients become quite an important event. And only the consistent, reproducible differences between the patients and controls may suggest the existence of a possible link.

I also do not agree with the notion that Crohn’s disease is more closely linked to diseases like leprosy rather than ulcerative colitis. There is no misdiagnosis between CD and leprosy at all. However, no matter how splendid the hospital, how good the doctor and how hard they try, there is always a portion of cases Non-Differentiable as either CD or UC. In addition, CD and UC but not leprosy also shared many similarities in epidemiological distribution, treatments, etc.”
 
If people are helped through antibiotics, and they are, you linked a single study, cherry picked.
Are you referring “cherry picked” to the citation in my early post (#264) of the study by Selby W, et al. (Antibiotics in Crohn's Disease Study Group. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology. 2007 Jun;132(7):2313-9) that failed to show sustained benefits by the antibiotics on MAP? You should realize that this is a prospective, parallel, placebo-controlled, double-blind, randomized trial with 2 years of treatment with a combination of clarithromycin, rifabutin, and clofazimine and a further year of follow-up, thus the most strictly controlled large-scale, long-term study in this regard. Yes, there were multiple open-labeled studies showing a wonderful effect with the same treatment for just a couple of months. However, which one would be more reliable? The same would be for the study on pig whipworms as discussed in this forum. Multiple open-label studies showed pretty good efficacy, but the company still terminated the trial after an interim analysis of the double-blinded study that failed to show the efficacy. In your opinion, which study should we choose and which results should we believe?
 
Are you referring “cherry picked” to the citation in my early post (#264) of the study by Selby W, et al. (Antibiotics in Crohn's Disease Study Group. Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease. Gastroenterology. 2007 Jun;132(7):2313-9) that failed to show sustained benefits by the antibiotics on MAP? You should realize that this is a prospective, parallel, placebo-controlled, double-blind, randomized trial with 2 years of treatment with a combination of clarithromycin, rifabutin, and clofazimine and a further year of follow-up, thus the most strictly controlled large-scale, long-term study in this regard. Yes, there were multiple open-labeled studies showing a wonderful effect with the same treatment for just a couple of months. However, which one would be more reliable? The same would be for the study on pig whipworms as discussed in this forum. Multiple open-label studies showed pretty good efficacy, but the company still terminated the trial after an interim analysis of the double-blinded study that failed to show the efficacy. In your opinion, which study should we choose and which results should we believe?
Yes I am, you cherry picked it. I can't discuss stuff with you because you cherry pick studies.

Same trial, completely different conclusion.
http://www.ncbi.nlm.nih.gov/pubmed/17369114

You could have easily picked that study...but you didn't.

A lot of things also went wrong in that cherry picked study...anyway.


Regardless, AIEC is very common in ileal crohn's disease. The conclusion in the cherry picked study was that antibiotics effective against gram- AIEC would be preferrable, and they probably are for people with ileal disease with granuloma.

Many trials done with cipro show success, cipro is quite effective against gram-, since many gram- live in biofilms, they are hard to eradicate, many many bacteria are extremely resistant to current day antibiotics. You are welcome to ignore those studies, I expect nothing less, you ignored half the data I present you, so why not add some more.

Part of the reason studies are so inconclusive, is because, like many people have said before, crohn's disease, crohn's collitis, collitis, are probably not the same diseases. And it is very unlikely that someone with colon involvement has the same disesase as someone with ileal disease, there are no peyer's patches in the colon, one of the first signs of crohn's disease in ileal patients, is inflammation of peyer's patches, my guess is because antigens are translocating and inflitrating M cells. The fact most crohn's disease ileal cases happen around the ages when peyer's patches are most active, is probably not an accident. There is a reason why crohn's disease manifsts itself at a certain age, it's clearly happening around 11-18 in most people. I don't have the numbers in front of me, around puberty.

Again........different diseases. Within crohn's disease there are probably different diseases, my guess is someone with crohn's colitis without granuloma does not have the same disease as someone with ileal involvement /inflammation of peyer's patches and granuloma. My guess is they are not the same disease. And UC is a very very different disease form crohn's disease.

If you bunch all these people up in the same studies, like some have done, yes you'll get studies that show great benefit and some that are not. Some people are extremely good candidates for antibiotics, ileal involvement, response to infliximab, granuloma, someone with crohn's collitis for example would not be a good candidate for those same studies.

But since some............."experts"..........like to bunch all the disesases together, uner the unfortunate IBD term, ppl are not getting individualised treatment. I am hardly the first person who has said that crohn's disesase should be divided into categories based on endoscopic and histological findings.
 
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I don't know why you focus on MAP all the time either. No one has said that MAP is causative in crohn's disease. What people who believe in an infectious agent often argue is that we have very specific genetic deficiencies that leave us vulnerable to intracellular pathogens, in patients all around the globe, it's no longer the case that asian patients are exempt from crohn's disease predisposition, studies have found predisposition to autophagy genes in asian patients also.

Autophagy is essential to clearing intracellular pathogens. That we would be prone to intestinal infections would be extremely normal considering many of us have NOD2 / ATG16L1 / IRGM / IL23 anomalies.

You can not ignore autophagy and macrophage disregulation in crohn's disease, it is a major part of the disease and one of it's major functions is clearing intracellular pathogens.

If you want to argue against bacterial involvment, then argue not just against MAP, argue against the studies that have shown AIEC, klebsiella, Listeria, Yersinia DNA in crohn's disease patients.....people with immunodeficiences are not vulnerable to one single bacteria.
 
So in your eye, a retrospective study of 39 patients is superior to a 3 year prospective, parallel, placebo-controlled, double-blind, randomized trial of 230 patients. I have nothing to say.
I don't care what is "superior". I don't base my conclusions on one single study.

The idea that there is bacterial involvment is crohn's disease is not based on a single study. It's based on genetic findings that are all related to bacterial clearance, it's based on PCR tests, it's based on the presence of granuloma, it's based on limited success with antiboitics, disease clustering, history of other diseases, etc.

No one has said that the causative agent is, with 100% certainty, bacteria. But it should damn well be considered considering the mountain of evidence regarding autophagy, macrophage deficiencies, in vivo tests that show lack of bacterial clearance, in vitro tests, enhanced macrophage function with vitamin D, the benefit of vitamin D on both remission rates and stimulation of NOD2 to ATG genes.

How much evidence do you need to admit......or at the very least consider....that bacterial involvement is present. You can't be this stubborn.
 
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The idea that bacteria are behind the inflammation is not a new idea etiher. Dalziel in 1913 in the BMJ considered bacteria as an agent behind the inflammation in crohn's disease, he called it chronic enteritis. Since they could check for TB back then, they ruled out TB, but they never ruled out bacterial involvement, in fact he suggested bacterial involvement, at that time they had no DNA tests like we have now.
 
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